Our recent studies of X-linked agammaglobulinemia (XLA) have led to a new characterization of pre-B cells as found in the patients and in normal individuals. Based on these studies, we propose that early, normal, pre-B cells produce the constant (C) region of mu heavy (H) chain without an associated variable (V) region. In patients with XLA who lack B lymphocytes (Most patients), the pre-B cells fail to proceed beyond this stage of early pre-B cells, that is, they never express V region. We have now found pre-B cell analogues from normal individuals which are analogous to the pre-B cells from XLA, that is, cells producing Cmu without V region. We will characterize the RNA produced by these cells, and the immunoglobulin H chain genes to determine whether the molecules produced represent Cmu alone, or Cmu in association with D and J regions. A C-D-J molecule, including the third hypervariable region, may represent a primordial antibody molecule, with degeneracy of receptor specificity. A few patients with XLA develop B lymphocytes which circulate in peripheral blood. Our recent re-examination of these cells indicate that they are not true B lymphocytes, in that they produce mu and delta heavy chain without associated light (L) chain. We will examine the molecular basis for this failure to produce L chains, which may result from failure to (or aberrant) translocate L chain V region gene, or from aberrant RNA processing. As a unifying hypothesis for these two forms of XLA, which may occur in the same family, we will be directly testing whether XLA may result from an inability to translocate (rearrange) V region genes, affecting H chains in some patients, L chains in others.